The regulation of transcription of the human glucocorticoid receptor (GR) gene was investigated through transient expression assays using promoter chimeras in CV-l, NIH3T3 and HeLa cells. Dexamethasone (DEX) induced a consistent but very modest decline in promoter activity in NIH3T3 and CV-l cells. Surprisingly, promoter activity increased in HeLa with DEX. Forskolin also enhanced promoter activity. Phorbol ester (TPA) treatment and co-transfection with c-Jun resulted in an increase in activity in cv-i cells. The TPA-induced enhancement of activity is blunted by DEX-GR. These data show the convergence of three different signaling pathways on the OR promoter. We have continued the genome search for a predisposing locus to manic- depressive illness. Markers have now been typed on chromosomes 2, 3, 4, 5, 7, 9, lop, 11p, 20 and 22. Positive lods have been obtained but exhaustive analyses of markers within these regions fail to support linkage. The mineralocorticoid receptor (MR) has been mapped to 4q, by genetic linkage we found that MR is located between GYPA/B and FGA/B and closely linked to these markers. New polymorphism was also found at the vesicular monoamine transporter gene. A new single stranded conformation polymorphism (SSCP) was found in GR which corresponds to a single nucleotide change in the An 768 codon.